Study protocol
The RISING-STAR study started on March 2, 2020 with protocol version 1.1. The recruitment was completed on August 31, 2020.
This was a multicenter, open-label, non-randomized, exploratory, prospective, interventional study (Figure 1). The study was conducted at the University Hospital Kyoto Prefectural University of Medicine as the core facility and at six facilities with specialized diabetes outpatient services located in the same Kansai area in Japan as the core facility. No changes to the methods after pilot trial commencement, including eligibility criteria, have been planned. Subjects were stratified into two groups based on the ratio of basal insulin (Basal) to TDD (Basal/TDD, <0.4 [Group A] or >0.4 [group B]). At the time of obtaining consent, participants were asked about their insulin use in the previous 24 h, with respect to basal and additional insulin amounts for the previous day. The sum of the basal and additional insulin doses was defined as the total insulin dose. If the basal insulin dose was 40% of the total insulin dose, the participant was assigned to Group B. If the basal insulin dose was less than 40% of the total insulin dose, the participant was assigned to Group A. Instructions provided to the study subjects are found in Table 1.
Table 1. Therapy protocol
![](https://myfiles.space/user_files/58653_1b1c6aeb34a62c68/58653_custom_files/img1604588106.png)
A pre-observation period of 4 weeks was established before the intervention (administration of 5 mg dapagliflozin). During this period, fasting plasma beta-hydroxybutyric acid (BOHB), flash glucose monitoring (FGM), and self-monitoring of blood glucose (SMBG) were measured and recorded. The start of dapagliflozin administration was set as day 0 of the observation period. The study subjects visited the research institutions four times; at weeks -4, 0, 2, and 4. The study subjects were issued a digital camera and instructed to take a picture of each meal they ate throughout the observation period.
[Group A] Study subjects who reduced bolus insulin dose by 10%
Subjects whose basal/TDD ratio was <0.4 were instructed not to reduce the basal insulin dose but to reduce the bolus insulin dose by 10%. The 10% reduction of the bolus insulin dose was based on a 90% carbohydrate insulin ratio (CIR) and was rounded to the nearest whole number in case of insulin therapy with multiple daily injections (MDI); alternatively, it was rounded down to two decimal places in case of continuous subcutaneous insulin infusion (CSII). The study subjects were instructed to follow this instruction for 3 days from the start of the intervention. After the fourth day, subjects were able to titrate both basal and bolus doses according to the “Algorithm for Basal Insulin Titration after SGLT2 Administration (Figure 2)” and “Algorithm for Bolus Insulin Titration after SGLT2 Administration (Figure 3).”
[Group B] Study subjects who reduced basal insulin by 10%
Study subjects whose basal/TDD was >0.4 were instructed to reduce their total insulin dose by 10%, reducing the basal insulin dose only. The dose of basal insulin was rounded down to one decimal place in case of MDI or to two decimal places in case of CSII. The study subjects were instructed to follow this instruction for 3 days from the start of the intervention. After the fourth day, subjects were able to titrate both basal and bolus doses according to the “Algorithm for Basal Insulin Titration after SGLT2 Administration (Figure 2)” and “Algorithm for Bolus Insulin Titration after SGLT2 Administration (Figure 3).”
Eligibility criteria
In line with the objectives of the study and to ensure the safety of the subjects, the inclusion and exclusion criteria explained in Table 2 were established. To appropriately evaluate the efficacy of the study drugs, patients requiring a legal representative were excluded.
Table 2. Inclusion and Exclusion Criteria
Inclusion Criteria
![](https://myfiles.space/user_files/58653_1b1c6aeb34a62c68/58653_custom_files/img1604588164.png)
Rationale for the inclusion criteria:
1-3: for the appropriate evaluation of the efficacy outcomes in the RISING-STAR study.
4: for the safety of the study subjects in the real-world situation.
5: for the participation of the study subjects by their free will.
Exclusion Criteria
![](https://myfiles.space/user_files/58653_1b1c6aeb34a62c68/58653_custom_files/img1604588191.png)
Observations
Observations and the schedule are shown in Tables 3 and 4. In principle, the study subjects visited the research institutions, and at every visit, blood tests (fasting) and urine tests (spot) were performed. Investigators collected and entered the examination results listed in Table 3 in the case report form (CRF) and sent the CRF to the Data Center. Adverse events were followed as safety endpoints throughout the study. The items that the study subjects measured by themselves were recorded on specific documents and sent to the Data Center via the investigators. No changes to pilot trial assessments or measurements after pilot trial commencement, including eligibility criteria, have been planned.
Table 3. Observation items
1. Eligibility information
Observation point
|
At consenting, enrollment
|
Observation item
|
sex, age/date of birth, inclusion criteria, exclusion criteria, date of giving consent, total daily insulin dose (TDD), basal insulin dose (Basal), bolus insulin dose, HbA1c
|
2. Background information
Observation point
|
week -4
|
Observation item
|
height, age, gender, presence/absence of smoking habit, presence/absence of drinking habit, wakeup time, bedtime, comorbidity (presence/absence or history of macrovascular/microvascular disease, dyslipidemia, hypertension, hepatic disease), information regarding kinds of medication* (medicine for hypertension, dyslipidemia, or diabetes mellitus), type and dose of insulin, allergy
|
* obtained by calculation
Observation point
|
week -4, week 0, week 2 (optional), week 4
|
Observation item
|
body temperature, blood pressure (sitting position, office blood pressure), pulse rate, body weight, body mass index*, body composition (skeletal muscle mass, body fat mass)
|
* obtained by calculation
4. Medication information (except study agent and insulin)
Observation point
|
week -4, week 0, week 2 (optional), week 4
|
Observation item
|
presence/absence and content of change in type or dose of medication
|
5. Medication information (study agent, insulin)
Observation point
|
throughout observation period
|
Observation item
|
presence/absence of medication of study agent
type and dose of insulin
* study subjects self-record in a diary
|
Observation point
|
week -4, week 0, week 2 (optional), week 4
|
Observation item
|
red blood cell count, white blood cell count, hemoglobin, hematocrit, blood platelet count, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase, lactose dehydrogenase, alkaline phosphatase, gamma-glutamyl transferase, urinalysis, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, blood urea nitrogen, creatinine (Cre), estimated glomerular filtration rate, HbA1c (or glycoalbumin), plasma glucose, serum albumin (Alb)
|
Observation point
|
week 0, week 4
|
Observation item
|
brain natriuretic peptide, C-reactive protein, C-reactive protein index
|
Observation point
|
week -4, week 0, week 2 (optional), week 4
|
Observation item
|
specific gravity, pH, protein, glucose, ketone body, occult blood, urobilinogen, bilirubin, u-mAlb, U-Cre, U-mAlb/Cre ratio
|
8. Special blood tests (fasting, using residual sample of “6. Blood tests”)
Observation point
|
week 0, week 4
|
Observation item
|
total ketone body, beta-hydroxybutyric acid, acetoacetic acid, plasma microRNA
|
9. Ultrasound cardiography (UCG)
Observation point
|
week -4, week 4
|
Observation item
|
ultrasound cardiography (early diastolic filling velocity, atrial filling velocity, E/A, e', E/e', DT, IVRT, TR, LVEF, LVEDV, LVESV, LAVI, LVDd, LVDs)
|
10. Quality-of-life score (questionnaire to whom the study subjects directly answer)
Observation point
|
week -4, week 0, week 4
|
Observation item
|
DTSQs (The Diabetes Treatment Satisfaction Questionnaire, status version) score; measures treatment satisfaction specific to diabetes mellitus, widely used around the world, consists of 8 questions.
|
11. Other items the study subjects measure by themselves 1
Observation point
|
throughout week -4 to week 0, week 0 to week 4
Study subjects will use the Freestyle Libre (Abbott Japan) for flash glucose monitoring (FGM) after receiving full explanation of how to use it. Since the sensor of the Freestyle Libre can be used for 2 weeks (14 days), investigators will give 2 sensors to each study subject in advance of each period. Study subjects will change and install a sensor every 2 weeks.
The data which the study subjects measure by themselves are recorded in the study subjects’ diaries.
|
Observation item
|
- Fasting plasma beta-hydroxybutyric acid (ketone body)
Study subjects will measure ketone bodies once daily before breakfast at home using the Freestyle Libre. Study subjects will also measure ketone bodies at will at physical deconditioning, sick days, or onset of symptoms suggesting ketoacidosis.
Study subjects will measure plasma glucose continuously at home using the Freestyle Libre.
- Plasma glucose (self-monitoring of blood glucose; SMBG)
Study subjects will conduct SMBG 4 times per day (before breakfast, before lunch, before dinner, and before bedtime) and upon the awareness of hypoglycemic symptoms or at FGM values of less than 70 mg/dL at home using the Freestyle Libre.
- Dose of insulin
- Awareness of hypoglycemia
|
12. Other items the study subjects measure by themselves 2
Observation point
|
throughout observation period
|
Observation item
|
- diet and relevant information
Study subjects will record their diet and relevant information every day throughout the observation period using software.
- gender, age, height, target body weight, activities of daily life: prespecified value (enter once)
- body weight, percent body fat, body water, alcohol intake, confectionery intake, staple food intake, main dish intake, side dish intake, milk product intake, fruit intake, number of steps (every day)
- energy, protein, lipid, carbohydrate, dietary fiber, sugar (every meal)
|
Observation item
|
- Fasting plasma beta-hydroxybutyric acid (ketone body)
Study subjects will measure ketone bodies once daily before breakfast at home using the Freestyle Libre. Study subjects will also measure ketone bodies at will at physical deconditioning, sick days, or onset of symptoms suggesting ketoacidosis.
Study subjects will measure plasma glucose continuously at home using the Freestyle Libre.
Study subjects will conduct SMBG 4 times per day (before breakfast, before lunch, before dinner, and before bedtime) and upon awareness of hypoglycemic symptoms or at FGM values of less than 70 mg/dL at home using the Freestyle Libre.
- Dose of insulin
- Awareness of hypoglycemia
|
13. Adverse events and diseases or the like
Observation point
|
throughout observation period
|
Observation item
|
Classification, outcome, severity, relationship, etc., of adverse event and disease or the like.
Adverse events and diseases or the like are observed throughout the study. Adverse events and diseases or the like include medication side-effects and clinically significant abnormal fluctuations in test results. Investigators will collect information on the presence/absence of hypoglycemia, hypoglycemia, and other adverse events and diseases or the like by interview at every observation point. Any occurrence of adverse events and diseases or the like are recorded into the case report form. Study subjects will be further followed up with if necessary.
*The classification of adverse events and disease or the like is based on MedDRA/J.
Refer “10. Safety evaluation analysis”
|
Data management and monitoring
Written informed consent was obtained from all participants. Linkable anonymization using the central registration number was used to identify subjects. Data collection and management were carried out by third-party entities to avoid bias. Data management was be performed by Soiken Inc. (Data Center). The Data Center prepared a procedure manual for data management. The Data Center’s approval was required prior to sending any data related to the subjects in an electronic format. If data were transmitted over an unsecured electronic network, the data were encoded at the source. The investigators were responsible for appropriate storage of the correspondence table prepared by them to identify the subjects, in accordance with the procedures at the particular research institution. This correspondence table will be retained for 5 years after the completion of the RISING-STAR study. Appropriate measures, such as encoding or deletion, will be taken to ensure that the subjects cannot be identified, in accordance with applicable laws and regulations.
The Data Center will monitor the RISING-STAR study to manage and ensure quality. The monitoring manager will monitor subjects in accordance with the prescribed manual on monitoring. For data quality management, the principal investigator and central committee will confirm the progress of the RISING-STAR study as necessary through the Data Center to ensure conformance with the protocol and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (February 28, 2017; Ministry of Education, Culture, Sports, Science and Technology/Ministry of Health, Labor and Welfare) and the Clinical Trials Act (April 14, 2017; Ministry of Education, Culture, Sports, Science and Technology/Ministry of Health, Labor and Welfare).
Primary endpoints
The frequency of hypoglycemic episodes per day was confirmed using SMBG during the intervention period (administration of 5 mg dapagliflozin).
Secondary endpoints
- Frequency of ketosis before and after the intervention
Ketosis was defined as plasma BOHB ≥600 μmol/L [27-28]. The frequency of ketosis was defined as the proportion of the number of days in which ketosis occurs in the study subjects during the pre-observation period and the observation period after the intervention.
- Frequency of hypoglycemic episodes per day before and after the intervention detected by FGM
- Change and difference in change between intervention groups on the following items, before and after the intervention
3-1. Fasting plasma beta-hydroxybutyric acid (ketone body)
3-2. Basal insulin dose*, bolus insulin dose*, total insulin dose*, CIR, and insulin sensitivity factor (ISF)
3-3. Time spent in hypoglycemia (percentage of time spent in glucose range ≤70 mg/dL), time spent in hyperglycemia (percentage of time spent in glucose range ≥70 mg/dL), and time spent in nocturnal hypoglycemia, detected using FGM
3-4. Vital signs: blood pressure, pulse rate
3-5. BMI, skeletal muscle mass†, fat mass†
3-6. Blood biomarkers: red blood cell count, white blood cell count, hemoglobin, hematocrit, blood platelet count, hepatic enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactose dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyl transferase), urinalysis, total cholesterol (T-Chol), high-density lipoprotein, low-density lipoprotein, triglycerides (TG), blood urea nitrogen, creatinine (Cre), estimated glomerular filtration rate (eGFR), brain natriuretic peptide (BNP)†, HbA1c (or glycoalbumin), plasma glucose, albumin, C-reactive protein (CRP)†, and CRP index†
3-7. Urine biomarkers: specific gravity, pH, protein, glucose, ketone body, occult blood, urobilinogen, bilirubin, microalbumin, creatinine, and microalbumin-creatinine ratio
3-8. Total ketone bodies†, beta-hydroxybutyric acid†, and acetoacetic acid†
3-9. Quality-of-life score (DTSQ)
* Measured by daily dose, † measured at visits 2 and 4 only
Safety endpoints
Frequency of adverse events (including frequency of hypoglycemic episodes detected by FGM).
Exploratory endpoints
Correlation between changes in dietary habits, dietary content, and nutrient intake and changes in fasting plasma β-hydroxybutyric acid levels.
Change in plasma microRNA profile.
Change in cardiac function estimated by ultrasonic echocardiography (UCG).
Rationale underlying the sample size
The RISING-STAR study was designed as an exploratory study, and no prior studies have reported the frequency of hypoglycemia after the administration of SGLT2 inhibitors. We hypothesized that the frequency of hypoglycemic episodes per day would increase after the administration of an SGLT2 inhibitor if the dose of basal insulin was not titrated. The baseline frequency of hypoglycemia was set as 7 ± 6 times/month when insulin glargine was used in patients with type 1 diabetes [29]. The minimum sample size required to achieve a significance of 0.05 for a one-sided t-test with a statistical power of 80% was determined. When the sample size was 26 patients in one group, the percent increase in hypoglycemia was more than 60%, and the sample size was estimated to be sufficient. With an estimated dropout rate of 10%, the planned number of subjects (60 subjects, 30 in each group) was thought to have enough statistical power for an increased hypoglycemic frequency of more than 60% (11.2 ± 6 times/month) in Group A (Basal/TDD <0.4, the study subjects were instructed to not reduce basal insulin dose but instructed to reduce bolus insulin dose by 10%) from 7 ± 6 times/month in Group B (Basal/TDD > 0.4, the study subjects were instructed to reduce basal insulin by 10%).
The RISING-STAR study will be conducted at seven research institutions, where a total of 350 patients with type 1 diabetes are being treated. From a previous survey, 30% of these patients were eligible for SGLT2 inhibitors as per the Japanese indications, meaning that approximately 100 patients could use an SGLT2 inhibitor with insulin. Among the 100 patients, all patients who sign a written consent form will be enrolled in the study and stratified into Group A (Basal/TDD < 0.4, subjects instructed to not reduce basal insulin dose but reduce bolus insulin dose by 10%) or Group B (Basal/TDD > 0.4, subjects instructed to reduce basal insulin by 10%). The proportion of patients who will consent is assumed to be 80%, and the proportion of patients who meet the inclusion criteria and none of the exclusion criteria is assumed to be 80%. Under these conditions, the target number of 60 study subjects is feasible.
Analysis of the primary endpoint
Summary statistics will be calculated for the number of hypoglycemic events per day (plasma glucose level defined by SMBG <70 mg/dL) during the intervention period (from baseline to week 4) using the full analysis set (FAS) as the main analysis set and the per protocol set for the sensibility analysis set. For comparisons between groups, a two-sample t-test and analysis of covariance will be conducted, and differences between the groups and their 95% confidence intervals will be calculated. HbA1c, age, and frequency of hypoglycemia (<70 mg/dL, confirmed by SMBG) per day during the pre-observation period before the intervention (week -4 to baseline) will be used as covariates in the analysis of covariance. If the data is not normally distributed, the summary statistics will be calculated after logarithmic transformation.
Analysis of the secondary endpoints
For the analysis of secondary endpoints 1 (frequency of ketosis) and 2 (frequency of hypoglycemia detected by FGM), summary statistics of measurements and changes will be calculated using the FAS during the pre-observation period before the intervention (week -4 to baseline), and the observation period after the intervention (baseline to week 4) in each group. For the measurements, a two-sample t-test will be used for comparisons between groups, and for the change, a one-sample t-test will be used for comparison in each group. If the data are not normally distributed, the summary statistics will be calculated after logarithmic transformation.
For the analysis of secondary endpoint 3, summary statistics will be calculated using the FAS for measurements at each observation point and change in the measurements from baseline to each observation point after the intervention. For the measurement, a two-sample t-test will be used for comparisons between groups, and for the change in the measurement, a one-sample t-test will be used for comparison in each group.
Analysis of the safety endpoints
For the analysis of the safety endpoints, a table of all adverse events and diseases or the like will be created for each group using the safety analysis set, and comparisons will be performed between groups as necessary using Fisher’s exact test.
Analysis of exploratory endpoints
For the analysis or correlation between changes in dietary habits, dietary content, nutrient intake, and changes in fasting plasma BOHB acid, the Spearman rank correlation coefficient and its 95% confidence interval will be calculated and evaluated for significance. The subjects will be instructed to take pictures of each of their meals using a digital camera. The stored images will be uploaded to a data cloud, and diabetologists will analyze the images according to the Standard Tables of Food Composition in Japan using a specialized application (Asken, Wit Co.; Orange, CA). The volumes and calories of carbohydrates, proteins, fats, and nutrient intakes will be calculated by the system and referred to as “online nutritional evaluation.”
Ethics
The protocol was approved by the Kyoto Prefectural University of Medicine Clinical Research Review Board (CRB5180001) and registered at jRCT (jRCTs051190114).
Table 4. Observation schedule
observation item
|
|
observation period / observation point
|
enrollment
|
week
-4*
|
baseline
week 0*
|
week 2
± 1 week
|
week 4
± 1 week
|
at
discontinuation
|
obtaining consent
|
○
|
|
|
|
|
|
①Eligibility information
|
○
|
|
|
|
|
|
②Background information
|
○
|
○
|
|
|
|
|
③Physical examination
|
|
○
|
○
|
△
|
○
|
△
|
④Medication information (except study agent and insulin)
|
|
○
|
○
|
△
|
○
|
△
|
⑤Medication information (study agent, insulin)
|
|
← ○ →
|
⑥Blood tests
|
|
○
|
○
|
△
|
○
|
△
|
⑦Urine tests
|
|
○
|
○
|
△
|
○
|
△
|
⑧Special blood tests
|
|
▲
|
▲
|
|
▲
|
▲
|
⑨UCG
|
|
○
|
|
|
○
|
△
|
⑩QOL score
|
|
○
|
○
|
|
○
|
|
⑪Other items the study subjects measure by themselves 1
|
|
28 days
〇
|
28 days
〇
|
|
⑫Other items the study subjects measure by themselves 2
|
|
← ○ →
|
⑬Adverse events and diseases or the like
|
|
← ○ →
|
○required
△optional
▲conduct if a residual sample exists
* Conducted before the start of the study agent administration
UCG, ultrasound cardiography; QOL, quality of life.